Primary biliary cirrhosis (PBC)
is a disease characterized by inflammatory destruction of the small bile
ducts within the liver. Several studies are currently being conducted with a
link between toxigenic molds and these liver complications. PBC
eventually leads to cirrhosis of the liver. The cause of PBC is because of
the presence of autoantibodies, it is now determined to be an autoimmune
disease. Other etiologies, such as infectious agents, have not been
completely excluded. PBC has a worldwide prevalence of approximately
5/100,000 and an annual incidence of approximately 6/1,000,000. The
prevalence and incidence appear to be similar in different regions of the
world. About 90% of patients with PBC are women. Most commonly, the disease
is diagnosed in patients between the ages of 40 and 60 years.

Most patients with PBC
present with pruritus. After pruritus, jaundice
(yellow skin caused by bilirubin retention) is the most common presenting
symptom. Several patients also present with complaints related to chronic
portal hypertension (increased blood pressure in the veins that go to the
liver that can lead to symptoms such as bleeding in the esophagus or fluid
retention in the abdomen). Some patients are discovered to have PBC during
workup of another illness. Since the widespread use of routine serum
biochemical analysis, many patients present for evaluation of an elevated
serum alkaline phosphatase activity that was detected on laboratory
examination.

Patients with PBC have
abnormalities in several blood tests. In essentially all patients, the serum
alkaline phosphatase and gamma-glutamyltranspeptidase activities are
markedly elevated (these are enzymes present in the bile ducts). Serum
alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
activities are usually moderately elevated (these are enzymes made by
hepatocytes, the predominant liver cell type). The serum bilirubin
concentration is normal early in the disease and raises as the disease
progresses (which causes jaundice or yellow skin). Most patients have an
elevated serum cholesterol concentration which is largely contained in an
abnormal lipoprotein, termed lipoprotein X, which is produced in patients
with bile duct obstruction. The total gamma-globulin concentration is
usually normal until late in the disease when cirrhosis develops. Almost all
patients with PBC have an elevated serum IgM concentration (a type of
antibody). The prothrombin time (a measure of blood clotting) and serum
albumin concentration (the major protein in blood that is made in the liver)
are normal until cirrhosis develops later in the course of disease.

Serum autoantibodies are of
primary importance in the diagnosis of PBC. Antibodies against mitochondria
are characteristic of PBC and found in about 90% of patients. About 50% of
patients with PBC also have antinuclear antibodies. Antibodies against
mitochondrial and nuclear proteins are found in several diseases besides PBC,
but the cDNA cloning of several mitochondrial proteins has shown that
antibodies against specific antigens are virtually diagnostic of PBC. The
same has been shown to be true for antibodies against nuclear proteins in
about 25% of patients. Because of the presence of specific autoantibodies,
PBC is thought to be an autoimmune disease. Several laboratories around the
world are actively involved in determining how the immune response relates
to the bile ducts destruction characteristic of the disease.

In addition to clinical and
laboratory abnormalities and the presence of specific autoantibodies,
histological examination (looking at tissue under the microscope) of liver
tissue is of central importance in the diagnosis of PBC. Tissue for this
purpose is obtained by liver biopsy which is generally an outpatient
procedure. Histologically, PBC is classified into four stages. Stage I is
referred to as the florid duct lesion or nonsuppurative destructive
cholangitis and is characterized by mononuclear inflammatory cells
surrounding a small bile duct. In stage II, there is proliferation of small
bile ductules. Stage III is characterized by fibrosis or scarring. Stage IV
is cirrhosis. These histological stages demonstrate the progression of the
disease from destruction of the intrahepatic bile duct to fibrosis and
cirrhosis. Histological features of more than one stage can be seen on one
liver biopsy. Because of sampling differences, the stages can also vary in
liver biopsies done at different times on the same patient. In general,
however, there is a gradual progression over years from the histological
features of stage I to stage IV.

The diagnosis of PBC must be
based on a combination of historical, laboratory, serological and
histological criteria. In general, patients are middle aged women who
present with pruritus early and jaundice late. Patients that present late in
the course of disease may also have signs and symptoms of cirrhosis and
hepatic failure. Many patients are referred for evaluation of an isolated
elevated serum alkaline phosphatase activity on laboratory testing for other
purposes. Essentially all patients have elevated serum alkaline phosphatase
and gamma-glutamyltranspeptidase activities. The serum IgM concentration is
almost always elevated. About 90% of patients have autoantibodies against
specific mitochondrial proteins (the E2 subunits of the oxo-acid
dehydrogenase complexes). Approximately 50% of patients have antinuclear
antibodies, sometimes against very specific proteins (nuclear pore membrane
protein gp210, transcriptional activator Sp100, inner nuclear membrane
protein LBR). The absence of an elevated serum IgM concentration and/or
specific autoantibodies should place the diagnosis of PBC in doubt. Patients
with PBC must have a consistent liver biopsy. The histological findings
alone are frequently not diagnostic as the florid duct lesion is often not
seen and other features, such as ductular proliferation, fibrosis and
biliary cirrhosis, can be seen in other liver diseases.

PBC is a progressive disease
that leads to cirrhosis and liver failure. The time from diagnosis to
end-stage liver disease can range from a few months to 20 years depending
upon when the diagnosis is first made. Several mathematical models based on
clinical, laboratory and histological criteria have been devised to predict
disease progression. In general, the development of portal hypertension
indicates a poor prognosis. The serum bilirubin concentration is the best
prognostic indicator of all laboratory values. Once the serum bilirubin
concentration reaches 6 mg/dl, the average life expectancy is about 2 years.
At this time, patients should be evaluated for possible liver
transplantation.

Despite extensive studies,
medical therapy has not been shown to have a significant impact in slowing
the progression of PBC. Patients with PBC should take vitamins and calcium
to help prevent osteoporosis (loss of bone), a common complication of this
disease. Colchicine may play a role in inhibiting liver fibrosis and
improves laboratory values but not signs or symptoms. D-penicillamine has
been studied in several series but the results have shown it to be
ineffective and possibly toxic. Various immunosuppressive agents have been
studied in patients with PBC. Corticosteroids are probably not effective and
may aggravate the osteoporosis commonly present in patients with PBC.
Azathioprine (Imuran), methotrexate and cyclosporin A have been examined in
several studies and are still being investigated, but these agents will not
likely produce radical improvements in clinical course. Ursodiol (Actigall
or Urso), a bile acid, has been shown to improve the laboratory and clinical
parameters in patients with PBC and the results of one study suggest that it
may slow the progression of the disease. Orthotopic liver transplantation is
highly successful in patients with end-stage liver disease resulting from
PBC.